In order to minimize problems associated with ketoacidosis, which results from an imbalance in ketone body synthesis and utilization, it is necessary to understand the mechanisms controlling ketogenesis. While ketogenic regulation probably involves several control points, recent reports support the hypothesis that a control site is located within the hydroxymethylglutaryl-Coenzyme A (HMG-CoA) cycle, which is the actual site of ketone body synthesis in liver. The precise location of the site of control within this cycle is unclear, as is the significance of control within the HMG-CoA cycle in comparison with that exerted at other regulatory sites. The availability of purified HMG-CoA synthase and HMG-CoA lyase will permit a detailed study of the active sites and the catalytic mechanisms of these enzymes. Such data, along with a detailed characterization of the enzyme proteins, will improve our understanding of how the HMG-CoA cycle may function in vivo and facilitate the design of experiments aimed at determining whether changes in enzyme activity occur upon transition from the normal to the diabetic state. Preparation of antibodies to purified HMG-CoA synthase and HMG-CoA lyase will permit sensitive immunoassays to be deveoped, which will be useful in detecting the possible alteration of levels of these enzymes in diabetes or hydroxymethylglutaric acidurea. The immunochemical approach will also be useful in exploring the possibility of a ketogenic enzyme complex and in testing whether hormonal conditions which markedly stimulate ketogenesis in cultured hepatocytes result in covalent modification of the ketogenic enzymes and modulation of their activity.